Defining a Dystonia Specific Spiking Signature in Cerebellar Nuclei Cells

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Project summary and significance: Dystonia is characterized by involuntary muscle contractions and is estimated to be the third most common movement disorder in the United States. Dystonia can be the primary symptom in patients of all ages or present as a secondary symptom in patients with neurodevelopmental and neurodegenerative disorders and affects function of many nodes in the motor circuit, including the thalamus, basal ganglia, motor cortex, and cerebellum. This neurological diversity – in addition to the genetic heterogeneity of hereditary dystonia – has made it difficult to pinpoint therapeutic targets. A better understanding of the pathophysiology of dystonia is indispensable to the development of more effective treatments. Recent studies suggest that cerebellar pathophysiology forms a shared mechanism for the inception of etiologically distinct dystonias; nearly all animal models with overt dystonia-like symptoms have abnormalities in the spiking activity of cerebellar neurons. Yet, the precise mechanism of cerebellar dysfunction in dystonia is enigmatic, especially because cerebellar pathophysiology is primarily known to cause other motor disorders, like ataxia and tremor. This Pathway to Independence Award proposal leverages quantitative, in vivo electrophysiology in genetic, developmental, and optogenetic mouse models of dystonia to define a dystonia-specific spiking signature in cerebellar output neurons, and to deduce the developmental divergence of cerebellar function between healthy and dystonic mice. This knowledge will provide a biomarker and therapeutic target for dystonia, which will be invaluable for designing new treatments that alleviate or prevent symptoms onset in patients or mutation carriers. Candidate and career development: Dr. Meike van der Heijden was trained in developmental neuroscience in the laboratory of Dr. Huda Zoghbi, where she used intersectional genetics to unveil the function and identity of brainstem respiratory neurons essential for postnatal survival. She then joined the laboratory of Dr. Roy Sillitoe, a world-leader in cerebellar neuroscience with a strong record of NIH funding, mentorship, and scientific leadership. Here, she developed an analytical platform and generated a database to assess spiking activity in cerebellar neurons across mouse models of cerebellar disease (dystonia, ataxia, tremor), and studied how impaired maturation of cerebellar Purkinje cell function leads to neurological deficits. In this proposal, Dr. Van der Heijden will build on her skills in in vivo electrophysiology, mouse genetics, and neuroanatomy and expand her analytical tool-kit, broaden her skills in unbiased quantitative motor function assessment, and acquire proficiency in acute manipulation of cerebellar circuits using optogenetics. All experiments will be conducted in the Neurological Research Institute, a collaborative research institute for clinical excellence and world-class neuroscience research built by Texas Children’s Hospital and Baylor College of Medicine in the heart of the Texas Medical Center. The professional training plan is designed to launch Dr. Van der Heijden’s career as a successful scientist focused on the understanding of cerebellar development in the pathophysiology of dystonia.